Method for preparing a solid sustained release form of a functionally active composition

ABSTRACT

The invention is a sustained release dosage or delivery form, such as a tablet, pill, granule or the like capable of providing sustained release of a functionally active ingredient and the method for its manufacture. The invention comprises a matrix of a polymer containing functionally active ingredient and an excipient shaped at or above the glass transition temperature of said polymer into a form such as a granule, tablet or the like. Preferably the excipient is a microcrystalline cellulose.

This is a continuation-in-part of copending U.S. application Ser. No.124,705 filed Nov. 24, 1987, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a method for preparing a dosage form, such asa tablet, a bead or the like, with a controlled and delayed release ofthe active ingredient and the controlled release dosage form made by theprocess.

It is known to produce solid pharmaceutical or other functionally activepreparations which ensure a sustained release of an active ingredientover a long period of time and thus ensure a constant concentration ofactive ingredient in the body. These delayed release forms make itpossible to reduce the number of doses of the drug to be administereddaily and thus simplify the treatment plan considerably. Usually delayedrelease tablets and capsules are provided with a coating which regulatesthe release of active ingredient.

One disadvantage of relying on coatings for the delayed release propertyis that any inadvertent puncture of the coating or division of thetablet critically affects the coating integrity or the total surfacearea of the tablet, that is, some of the barrier coating effectivenessis lost. As a result, the characteristics of the release of activeingredient are significantly altered, so that in many cases, the delayedrelease tablets no longer have the property of delayed and continuousrelease of an active ingredient.

In addition, tablets with score lines are known which enable the tabletsto be divided into partial doses in order to meet special therapeuticrequirements. Divisible tablets of this kind must, in particular,satisfy the requirement of being easy and safe to divide and of ensuringprecise dosage, even when broken into fragments.

Microencapsulated formulations do not wholly overcome the problem ofcontrolled release because the film-forming agent frequently forms acontinuous phase after a period of time making it impossible to maintainreproducible release rates. U.S. Pat. No. 4,716,041 to Kjornaes et al.teaches a microencapsulated formulation of a first, inner film-formingcoating, a second, outer film coating. The coated formulations aresubsequently heated to permit the inner film-forming coating to form acontinuous phase with uniform diffusion characteristics with time. Sucha multiple coating process adds to the expense of a formulation and doesnot overcome the problem of coating integrity for tablets, caplets andother dosage forms.

Orally administerable pharmaceutical preparations are known in which theactive substance is embedded in a polymer or matrix. The matrix slowlydissolves or erodes to release the pharmaceutically active ingredient.The feed formulations of pharmaceutical preparations of this kind arenormally produced by dissolving the active ingredient together with apolymer in a solvent, then evaporating the solvent and granulating thesolid mixture. Frequently the removal of the solvent and the granulationare carried out in a single operation by spray drying.

Pharmaceutical preparations of this type are intended for the purpose ofdistributing the active ingredient in a finely dispersed form throughthe polymer and increasing the surface area of the substance which is tobe dissolved, so as to accelerate and not delay the dissolving process.

U.S. Pat. No. 4,547,359 teaches that a divisible polyacrylate-basedtablet may be formed of a compressed composition comprising a finelydivided polyacrylate material having the active ingredient incorporatedtherein in molecular dispersion, and conventional tablet excipients.However, the patent teaches it is particularly important to use aspecific acrylate polymerized by emulsion polymerization and having aparticle size of about 140 nm. Polyacrylates prepared by other methods,such as by solution or block polymerization, are unsuitable for purposesof the invention. In order to ensure a delayed release of the activeingredient, the active ingredient embedded in the polyacrylate materialshould have diffusion coefficients of 10⁻⁵ to 10⁻⁷ cm² per hour.However, it is undesirable to restrict the pharmaceutically activecompounds to such a narrow range of diffusion coefficients.

U.S. Pat. No. 4,692,337 to Ukigaya et al. teaches that prior artformulations based on a water-insoluble or slightly water soluble matrixhave two disadvantages, the weight percentage of the matrix materialmust be 50% or more of the total weight, and that the rate of release ofthe medication rapidly decreases with time. Instead, the patent teachesdry mixing 100 parts of the active ingredient, theophylline, with 5 to200 parts of ethyl cellulose and compressing the mixture into tablets.

Polylactic acid (PLA) is a well-known biologically compatible, insolublepolymeric body employed for the sustained release of pharmaceuticalingredients. U.S. Pat. No. 4,357,312 teaches an implantable matrixsuitable for dispensing pharmaceutical ingredients in which thepharmaceutical ingredient is dissolved in a mixture of polylactic acid,solvent and water. Freezing the water creates channels, and subsequentdrying removes the solvent and water. The freezing conditions must becarefully controlled to make the release of the pharmaceuticalingredient uniform.

U.S. Pat. No. 4,659,558 discloses bioerodable polymers useful to formcoatings including polycarboxylic acids, polyamides, polylactic acid,polyglycolic acid and the like.

U.S. Pat. No. 4,666,702 teaches a drug delivery tablet containing acentral core and a coating which is a thermoplastic polymer, optionallypolylactic acid, nylon, polyglycolic acid and the like.

U.S. Pat. No. 4,652,441 teaches a microcapsule or bead suitable forcontrolled release of a water soluble pharmaceutical ingredientincluding an oil layer thickened with polylactic acid.

DESCRIPTION OF THE INVENTION

The present invention overcomes the disadvantages of the prior artprocesses. The invention is a method for preparing a sustained releasedosage or delivery form comprising blending a dosage amount of afunctionally active ingredient, an excipient and a polymer having aglass transition temperature of about 30° C. to about 150°C. into a feedformulation, said polymer being present in sufficient quantity to form amatrix containing the functionally active ingredient, processing atleast part of the feed formulation into a shaped form, and maintainingthe shaped form at or above the glass transition temperature of thepolymer for a sufficient time to provide a dosage form havingcontrolled, sustained release of the functionally active ingredient whenthe dosage form is administered.

DETAILED DESCRIPTION

Polymers are known to be useful for forming a matrix-type sustainedrelease dosage form. It has unexpectedly been found that a polymerhaving a glass transition temperature of about 30° C. to about 150° C.when maintained at or above the glass transition temperature in thepresence of an excipient and a functionally active ingredient is capableof a controlled, sustained release of the ingredient even when thepolymer comprises as little as 5% by weight. A polymer with a glasstransition temperature of about 40° C. to about 100° C. is preferredbecause of thermal stability and to provide a dosage form havingcontrolled sustained release property which does not requirerefrigeration during shipment or storage in tropic climates.

Although the invention is disclosed in terms of a unitary matrix tablet,the scope of the invention is intended to include any matrix form suchas a tablet, bead, microcapsule, densified nonpareil, pill, granule andthe like comprised of a functionally active ingredient, an excipient andany polymer or copolymer having a glass transition temperature fromabout 30° C. to about 150° C. The shaped form may subsequently bereprocessed into other dosage forms. For example, granules or smallpills may be processed into capsules, or may be tabletted.

Exemplary polymers or copolymers include low (branched) and high(linear) density polyethylene, polypropylene, poly(propylene/ethylene),polyisobutylene and higher homologs, poly(ethylene/isobutylene),poly(isoprene/isobutylene), ethylene/propylene/diene terpolymers (EPDM),methyl methacrylate polymers or copolymers from acrylic, or methacrylic,hydroxyalkyl acrylic or their methyl, ethyl or lauryl esters;polyacrylonitrile, vinyl acetate homopolymer or copolymers with vinylstearate, 2-ethylhexyl acrylate or ethyl acrylate, poly (vinyl butyral),poly(vegetable oil acid/ethylene diamine), polyoxymethylene,poly(ethylene oxide), cellulose acetate, acetate butyrate, propionate,acetate propionate, ethylcellulose, poly(ethylene terephthalate) orother polyesters of polyhydric alcohols and dicarboxylic acids,polyether, polyester or polyester/polyamide polyurethanes, polydimethyl-siloxane or other polysilicones, allyl diglycol carbonateprepolymers and furane resins. Additional polymers includemethylcellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose,hydroxyethylcellulose, cellulose acetate phthalate, polyvinyl acetatephthalate, polyvinyl alcohol, polyvinyl acetate, hydroxypropylmethylcellulose phthalate, polyhydroxy butyrate, polyhydroxy valerate,polycaprolactone, polylactic acid, polyglycolic acid, polylacticco-glycolic acid, polyglutamic acid, polyanhydrides, polyethyleneglycols and polypropylene glycols.

It is desirable for the polymers or copolymers to be eitherbiodegradable or bioerodable, and if to be used to control the releaseof pharmaceutically active compounds to be pharmaceutically acceptable.

Particularly desirable polymers or copolymers are polyisobutylene,polymers or copolymers of acrylic acid, methacrylic acid,hydroxyalkylacrylic acid, hydroxyalkylmethacrylic acid or their methyl,ethyl or lauryl esters. Other particularly desirable polymers includepoly(ethylene oxide), cellulose acetate, cellulose acetate butyrate,cellulose acetate proprionate, ethyl cellulose, polyesters of polyhydricalcohols and dicarboxylic acids, polyethers, cellulose acetatephthalate, dl-polylactic acid, polyglycolic acid,polylactic-polyglycolic copolymers, polycaprolactone,polyhydroxybutyrate, polyhydroxyvalerate and polyethylene glycols.

Any functionally active ingredient may be employed in the presentinvention, such as a pharmaceutically active ingredient, a flavor, afragrance, an insecticide, a herbicide, a veterinary product or thelike. Particularly desirable are pharmaceutically active ingredients,preferably pharmaceutically active ingredients selected from the groupconsisting of theophylline, quinidine sulfate, propranolol,chloropheniramine, testosterone and ethenyl estradiol.

Preferred commercial polymers are marketed under the name polyglycolicacid, poly(d,l)lactic acid and poly(d,l)lactic co-glycolic acid (85:15and 50:50 copolymers) by DuPont and are described in product bulletins"Glycolide S.G." May, 1988 and "Medisorb Bioresorbable Polymers" August,1988 and both are incorporated herein by reference. The polymers arerespectively also called poly(glycolide), poly(d,l-lactide) andpoly(D,L-lactide-co-glocolide) in Boehringer Ingelheim's productbulletin "Resorbable Polyesters" which is also incorporated herein byreference. The polymers may be obtained in a range of molecular weightsand inherent viscosities.

The polymer, such as dl-polylactic acid (PLA), can be introduced intothe feed formulation by any convenient method such as dry mixing, wetgranulation method or with a solvent system. In the latter method, thepolymer is dissolved in methylene chloride and then blended into thefunctionally active ingredient and excipient. A lubricant or otheradditive such as a colorant may be optionally added. The intended scopeof the invention includes any polymer having a glass transitiontemperature above about 30° C. However, polymers having a glasstransition temperature of over 150° C. may result in decomposition ofthe functionally active ingredient or of the excipient. A glasstransition temperature of less than 100° C. is preferable for use withmany thermally unstable ingredients, such as hydrates.

Heating a dosage form of a pharmaceutically active compound is contraryto the basic practice of pharmacology. One skilled in the art ofpharmacology avoids exposure of a dosage form to heat unless absolutelynecessary and unless explicitly required, and even then is cooled tominimize the heat to which the active compound is exposed.

Alternatively, the blend can be wet granulated with an aqueous latexdispersion of the polymer which is used as the binding solution. The airdried granulation is then blended with the lubricant and processed intoa shaped form.

Drug release is quite rapid for tabletted formulations made by either ofthese procedures with polylactic acid as the polymer. In less thanthirty minutes the drug is fully released into the dissolution medium.As the level of polymer is increased in the formulation from zeropercent, no significant retardation of release is achieved.

When no polymer is present in the tablet the tablet hardness decreasesas the time of heating increases. On the other hand, the hardnessincreases with tablets containing polymer as the time of heatingincreases. The hardness continuously increases with tablets containingat least 15% polymer. With tablets containing 5% to 10% polymer thehardness increases to a plateau. For the purpose of this invention allpercentages are expressed as weight percent. Any quantity of polymer maybe employed which is sufficient to form a matrix containing thefunctionally active ingredient, desirably 1% to 90% polymer issufficient, preferably 5% to 50% polymer. As used herein the term"maintaining the shaped form at or above the glass transitiontemperature" is intended to include heating by any conventional meansprior to administering but does not include thermal effects fromcompression alone.

Any convenient excipient may be employed in the feed formulation. Theexcipient may be employed for a single function such as a diluent, abinder, a lubricant, a disintegrant, an adsorbent, or for a combinationof functions. Common excipients such as lactose, dicalcium phosphate,calcium sulfate, sugars, microcrystalline cellulose, gums,methylcellulose, starch, polyvinylpyrrolidone, clay and the like may beselected by one skilled in the art to provide their usual contributionto the dosage form. The excipient may be employed in an amount varyingfrom 1% to about 90% by weight.

Particularly desirable excipients are marketed under the tradename ofAvicel brand microcrystalline cellulose by FMC Corporation.Microcrystalline cellulose is suitable for use as a binder, a diluentand as a disintegrant. The Avicel PH grades of microcrystallinecellulose are preferred for use in compression shaping. The product isporous which permits the microcrystalline cellulose to absorb a liquidingredient while remaining a free-flowing powder suitable to serve as afeed formulation for compression. Microcrystalline cellulose alsoprovides an intermediate disintegration rate between the rapiddisintegration rate of soluble excipients and the very slowdisintegration rate of insoluble excipients such as calcium sulfate.

A polymer, such as polylactic acid, is brittle below its glasstransition temperature. The glass transition temperature ("Tg") orsecond order transition temperature is the temperature at which apolymer changes from a brittle material (glassy state) to a rubberymaterial. The glass transition temperatures of polymers vary withmolecular weight. The glass transition, unlike a true thermodynamictransition, takes place over a temperature range of several degrees andis dependent upon the experimental method and the time scale used forits determination. The glass transition temperature can also vary withthe additives employed such as plasticizers, lubricants and the like.Below the transition, the majority of the polymer chains have a fixedconfiguration and little translation or rotation of chains takes place.Methods used to determine the glass transition temperature and thereported values for a large number of polymers are available in standardreferences employed by those skilled in the art. For the purpose of thisinvention the glass transition temperature shall include a temperaturebelow the melting point of a polymer at which the polymer ceases to be abrittle, glassy or crystalline solid and becomes rubbery or begins toflow.

Shaped forms of PLA, a functionally active ingredient and an excipientwhich have been processed into shaped forms and heated but not heated tothe glass transition temperature are usually erratic in their rate ofdissolution. Further, the hardness of the shaped forms decreases onheating below the glass transition temperature. However, when heated toor above their glass transition temperature the shaped forms form amatrix. They become consistent in their rate of dissolution and theirhardness increases. Further, the rate of dissolution decreases with anincrease of concentration of PLA and with the length of time the shapedforms are held at or above the glass transition temperature.

EXAMPLES

The following examples will explain to one skilled in the art the bestmodeof practicing the invention.

EXAMPLE 1

FEED FORMULATION PROCEDURES

Feed formulations were prepared containing 0%, 5%, 10% and 15% PLA. Thefunctionally active ingredient employed was theophylline and theexcipientemployed was Avicel PH 101 brand microcrystalline cellulose.0.5% magnesiumstearate was added as a lubricant. Dosage units of 300 mgcontaining 75 mg theophylline were compressed in a tablet press from afeed formulation containing as follows: 25% theophylline, 74.5%excipient and 0.5% lubricant (0% PLA); 25% theophylline, 69.5%excipient, 0.5% lubricant and 5% PLA; 25% theophylline, 64.5% excipient,0.5% lubricant and 10% PLA; and25% theophylline, 59.5% excipient, 0.5%lubricant and 15% PLA.

Although the invention is exemplified in terms of theophylline as thefunctionally active ingredient, microcrystalline cellulose as theexcipient and magnesium stearate as the lubricant, it will be clear tooneskilled in the art that any suitable functionally active ingredient,excipient or lubricant may be employed. A dosage amount of afunctionally active ingredient can vary over a wide range depending onactivity and time of sustained release. Generally 5% to about 50% of thefunctionally active ingredient will be contained in the matrix.

The feed formulations were prepared by two methods, dissolving the PLAin methylene chloride and adding the solution to the blend of thepharmaceutical ingredient and excipient (the "Organic" method), or byincorporating the PLA as an aqueous latex dispersion (the "Latex"method).The aqueous latices were prepared by emulsion of the organicsolution of the polymer with a Gaulin brand laboratory homogenizer.Subsequently, the organic solvent was removed by evaporation. After airdrying of the granules a lubricant was added to the feed formulation and300 mg tablets were formed by direct compression to about 5.5 kg. to 6kg. The PLA had a glass transition temperature of 55° C. to 57° C.

The hardness, friability and dissolution rates (U.S.P. Method II) oftablets were determined. The hardness and friability results arepresentedas Tables IA and IB. The dissolution data are presented as Runs2A to 6C. The numbers to the right of the decimal point indicate adifferent level of the variable under study in that series with Oindicating a control.

Run 1A: The percentage change of hardness on heating up to 24 hours at60° C. is presented as Table IA for tablets prepared by theOrganicmethod.

Run 1B: The friability of tablets prepared by the Organic method ispresented as Table IB as a function of PLA content and time of heating.

Dissolution Runs--Table II.

Run 2A: The rate of dissolution of theophylline is compared for 15% PLAtablets prepared by the solvent method heated for up to 12 hours at 40°C., less than the glass transition temperature.

Run 2B: The rate of dissolution of theophylline is compared for 15% PLAtablets prepared by the solvent method heated for up to 12 hours at 60°C., slightly above the glass transition temperature.

Run 2C: The rate of dissolution of theophylline is compared for 15% PLAtablets prepared by the solvent method heated for up to 24 hours at 60°C., slightly above the glass transition temperature.

Run 3A: The rate of dissolution of theophylline is compared for 5% PLAtablets prepared by the solvent method and heated at 60° C. for up to 24hours.

Run 3B: The rate of dissolution of theophylline is compared for 5% PLAtablets prepared by the solvent method and heated at 60° C. for up to 12hours.

Run 4: The rate of dissolution of theophylline from 10% PLA tabletsprepared by the Organic method and by the Aqueous Latex method arecompared after heating at 60° C. for 1 and 12 hours.

Run 5A: Rates of dissolution of theophylline are compared for tablets(Aqueous Latex method) containing 5%, 10% and 15% PLA and heated for 1hour at 60° C.

Run 5B: Rates of dissolution of theophylline are compared for tablets(Aqueous Latex method) containing 5%, 10% and 15% PLA and heated 6 hoursat 60° C.

Run 6A, 6B and 6C: Rates of dissolution of theophylline are compared fortablets containing 5%, 10% and 15% PLA after heating to 60° C. for up to24 hours.

From the above data it is clear that the rate of dissolution of apharmaceutically active ingredient can be controlled by the quantity ofpolylactic acid or other polymer incorporated into the feed formulation,the method of incorporation, and the time the tablets are maintained atorabove the glass transition temperature.

EXAMPLE 2

The influence of thermal treatment was determined on the dissolutionproperties of drugs from tablets containing various biodegradablepolymers. Unless specified otherwise, tablets were prepared fromformulation typically containing 25% of a functionally activeingredient, 60% Avicel PH 101 microcrystalline cellulose and 15%polymer. No lubricantwas employed.

The functionally active ingredient was mixed with the microcrystallinecellulose for 5 minutes. Granules were prepared by dissolving thepolymer in methylene chloride to distribute the polymer homogeneouslythroughout the matrix. The granules were air dried at 25° C. overnightand tablets were compressed to a weight of 500 mg with a Carverlaboratory press at 750 kg pressure. Heat treated tablets were heated at60° C. for 24 hours. Polymers employed were:

Poly-(dl-Lactide) High MW (UT), Tg 35° C.-40° C., [PLA-HMV];Poly-(dl-Lactide) Low MW, Tg 40° C.-45° C., [PLA-LMW]; Poly-(l-Lactide),Tg 55° C.-60° C., [L-PLA]; Polycaprolactone 300, mp 60° C.-62° C.,[PCL-300]; Polycaprolactone 700, mp 60° C.-62° C., [PCL-700]. Theabbreviations to be used herein for the polymers appear in squarebrackets.

Functionally active ingredients employed were:

Theophylline,

Chlorpheniramine Maleate,

Propanolol Hydrochloride, and

Quinidine Sulfate.

Rate of dissolution of matrix tablets with and without heat treatmentwere compared according to the method of Example 1. Results arepresented as Table III.

Runs 1 and 7 show the rate of dissolution is not a function of thepolymer alone, but that the excipient and/or functionally activeingredient also is a factor in controlling the rate of dissolution.

Run 8 is surprising in that the optically active polymer appearsineffective with the same formulation of ingredients that is effectivewith the racemic polymer. This run indicates that the effect of thermaltreatment is unexpected.

EXAMPLE 3

Tablets were prepared as before containing 25% theophylline, 60% AvicelPH 101 brand microcrystalline cellulose and 15% polymer. The polymerswere, Run 1, DuPont Medisorb 5050 brand of a 50:50 Poly(D,L)lacticco-glycolic acid polymer, [PLA:PGA], Tg 60° C.-65° C.; Run 2,polyethylene glycol mw 20,000, [PEG 20M]; and Run 3, Ritt Chemicalpolyisobutylene, [P1B], pour point 112.5° C. The percent theophyllinereleased with time (hours) was: Run 1, no heat treatment; 10%, 0.7 hour;17%, 1.3 hours; 25%, 2 hours; 39%, 4 hours; 49%, 6 hours and 71%, 12hours. Run 1, heated 24 hours at 67° C.; 10%, 0.7 hour;18%, 1.3 hours;32%, 2 hours; 39%, 4 hours; 47%, 6 hours; and 60%, 12 hours.

Run 2, no heat treatment; 10%, 0.5 hour; 17%, 1 hour, 29%, 2 hours; 88%,4 hours; and 100%, 6 hours. Run 2, heated 59° C., 24 hours; 10%, 0.5hour; 19%, 1 hour, 39%, 2 hours; 73%, 4 hours; and 94%, 6 hours. Herethe PEG tablets heat treated 24 hours at 59° C. are outstanding inthattheir rate of release of theophylline is a straight line function oftime.

Run 3, no heat treatment 50%, 0.5 hour; 77%, 1 hour; 98%, 2 hours; and100%, 4 hours.

Run 3, heated 60° C., 24 hours; 79%, 0.5 hour, 92%, 1 hour; 96%, 2hours; and 97%, 4 hours. Here the rate of release is initially greaterwith heat treatment but slows sufficiently so that the functionallyactiveingredient is still being released after the non-heat treatedtablet is exhausted.

                  TABLE IA                                                        ______________________________________                                        INFLUENCE OF 60° C. HEAT ON HARDNESS                                   PLA TABLET                                                                    Hours at                                                                              % of Initial Hardness                                                 60° C.                                                                         0% PLA   5% PLA     10% PLA 15% PLA                                   ______________________________________                                         0      100      100        100     100                                        1      93       104        100     103                                        3      94       104        NA      107                                        6      90       103        107     NA                                        12      85       104        107     108                                       24      87       104        105     110                                       ______________________________________                                    

                  TABLE IB                                                        ______________________________________                                        INFLUENCE OF 60° C. HEAT ON FRIABILITY                                 PLA TABLET                                                                    Hours at                                                                              % Loss of Friability                                                  60° C.                                                                         0% PLA   5% PLA     10% PLA 15% PLA                                   ______________________________________                                         1      0.10     0.09       0.05    0.04                                       3      0.13     0.08       NA      0.03                                       6      0.12     NA         0.05    0.04                                      12      0.13     0.06       0.04    0.03                                      24      0.12     0.06       0.04    0.02                                      ______________________________________                                    

                                      TABLE II                                    __________________________________________________________________________    RELEASE RATE OF TABLETS CONTAINING 25% THEOPHYLLINE                                           Percent Dissolved In                                             % PLA                                                                              Heat    %   %   %   %   %   %   %   %                                 Run                                                                              Polymer                                                                            Treated 0.5 hr.                                                                           1 hr.                                                                             2 hr.                                                                             3 hr.                                                                             6 hr.                                                                             12 hr.                                                                            24 hr.                                                                            48 hr.                            __________________________________________________________________________    2A.0                                                                             15%  None    98  100 100 100 100 100 --  --                                2A.1                                                                             15%  1 hr.                                                                             40° C.                                                                     28  39  52  --  65  80  --  --                                2A.2                                                                             15%  6 hr.                                                                             40° C.                                                                     25  32  42  --  62  80  --  --                                2A.3                                                                             15%  24 hr.                                                                            40° C.                                                                     24  30  40  --  61  78  --  --                                2B.0                                                                             15%  None    98  100 100 100 100 100 --  --                                2B.1                                                                             15%  1 hr.                                                                             60° C.                                                                     22  31  40  50  63  80  --  --                                2B.2                                                                             15%  6 hr.                                                                             60° C.                                                                     18  26  35  NA  51  66  --  --                                2B.3                                                                             15%  24 hr.                                                                            60° C.                                                                     16  23  33  NA  50  64  --  --                                2C.0                                                                             15%  None    98  100 100 100 100 --  --  --                                2C.1                                                                             15%  1 hr.                                                                             60° C.                                                                     22  30  40  45  64  82  95  --                                2C.2                                                                             15%  6 hr.                                                                             60° C.                                                                     18  26  35  --  52  64  88  --                                2C.3                                                                             15%  24 hr.                                                                            60° C.                                                                     16  23  33  --  50  63  79  --                                3A.0                                                                              5%  None    NA  98  100 100 100 100 --  --                                3A.1                                                                              5%  1 hr.                                                                             60° C.                                                                     --  27  45  59  81  86  99  --                                3A.2                                                                              5%  12 hr.                                                                            60° C.                                                                     --  26  44  58  80  85  98  --                                3A.3                                                                              5%  24 hr.                                                                            60° C.                                                                     --  26  43  58  80  84  99  --                                3B.0                                                                              5%  None    98  100 100 100 100 100 --  --                                3B.1                                                                              5%  1 hr.                                                                             60° C.                                                                     33  50  59  79  82  93  --  --                                3B.2                                                                              5%  12 hr.                                                                            60° C.                                                                     32  44  58  79  80  93  --  --                                3B.3                                                                              5%  24 hr.                                                                            60° C.                                                                     31  --  --  78  80  88  --  --                                4L.1                                                                             10%  1 hr.                                                                             60° C.                                                                     21  --  74  --  --  92  --  --                                4L.2                                                                             10%  12 hr.                                                                            60° C.                                                                     20  25  58  --  --  91  --  --                                4O.1                                                                             10%  1 hr.                                                                             60° C.                                                                     20  25  45  --  --  80  --  --                                4O.2                                                                             10%  12 hr.                                                                            60° C.                                                                     19  24  --  --  --  68  --  --                                5A.1                                                                              5%  1 hr.                                                                             60° C.                                                                     --  58  85  86  --  100 100 100                               5A.2                                                                             10%  1 hr.                                                                             60° C.                                                                     --  22  43  67  --  75  100 100                               5A.3                                                                             15%  1 hr.                                                                             60° C.                                                                     --   0  18  20  --  26  68  76                                5B.1                                                                              5%  6 hr.                                                                             60° C.                                                                     24  --   46*                                                                              80  --  85  84  --                                5B.2                                                                             10%  6 hr.                                                                             60° C.                                                                     20  --    38*                                                                             55  --  85  85  --                                5B.3                                                                             15%  6 hr.                                                                             60° C.                                                                      9  --   21*                                                                              25  --  61  78  --                                6A.1                                                                              5%  1 hr.                                                                             60° C.                                                                     58  --   90*                                                                              91  --  100 --  --                                6A.2                                                                              5%  6 hr.                                                                             60° C.                                                                     24  --   52*                                                                              80  --  92  --  --                                6A.3                                                                              5%  12 hr.                                                                            60° C.                                                                     23  --   40*                                                                              63  --  92  --  --                                6A.4                                                                              5%  24 hr.                                                                            60° C.                                                                     22  --   40*                                                                              53  --  88  --  --                                6B.1                                                                             10%  1 hr.                                                                             60° C.                                                                     --  21   46*                                                                              73  --  93  --  --                                6B.2                                                                             10%  6 hr.                                                                             60° C.                                                                     --  18   37*                                                                              52  --  91  --  --                                6B.3                                                                             10%  24 hr.                                                                            60° C.                                                                     --  16   31*                                                                              43  --  81  --  --                                6C.1                                                                             15%  1 hr.                                                                             60° C.                                                                     10  --  --  32  --  69  82  98                                6C.2                                                                             15%  6 hr.                                                                             60° C.                                                                     10  --  --  32  --  68  82  98                                6C.3                                                                             15%  12 hr.                                                                            60° C.                                                                     10  --  --  32  --  68  82  97                                6C.4                                                                             15%  24 hr.                                                                            60° C.                                                                     10  --  --  32  --  63  82  98                                __________________________________________________________________________    *11/2 hour                                                                

                                      TABLE III                                   __________________________________________________________________________    EFFECT OF HEAT TREATMENT ON RATE OF DISSOLUTION                               OF FUNCTIONALLY ACTIVE INGREDIENTS (FIA) FROM POLYMERS                                              Percent Dissolved In                                                     Heat %   %   %   %   %   %                                   Run                                                                              Polymer                                                                              FAI    Treated                                                                            0.5 hr.                                                                           1 hr.                                                                             2 hr.                                                                             4 hr.                                                                             6 hr.                                                                             14 hr.                              __________________________________________________________________________    1  PLA(LMW)                                                                             Theophylline                                                                         N    85  98  103 104 --  --                                                   Y    52  85  100 105 --  --                                  2  PLA(300)                                                                             Theophylline                                                                         N    42  60  81  96  102 104                                                  Y    20  32  47  63  73  92                                  3  PCL(700)                                                                             Theophylline                                                                         N    15  21  32  43  53  73                                                   Y     8  13  19  27  33  44                                  4  PLA(HMW)                                                                             Chlorphenir-                                                                         N    25  42  66  91  100 105                                           amine  Y    19  28  47  68  88  104                                 5  PLA(HMW)                                                                             Quinidine                                                                            N    15  25  37  54  66  87                                            Sulfate                                                                              Y    11  16  25  36  48  64                                  6  PLA(HMW)                                                                             Propanolol                                                                           N    43  59  79  98  101                                                      Y    26  39  58  77  90                                      7  PLA(LMW)                                                                             60% Theo-                                                                            N    42  66  93  100 102 103                                           phylline*                                                                            Y    21  42  74  97  101 103                                 8  LPLA   Theophylline                                                                         N    86  99  100 100                                                          Y    86  98  100 100                                         __________________________________________________________________________    *60% Theophylline, 25% excipient, 15% polymer                             

We claim:
 1. A method for preparing a sustained release dosage form comprising blending into a feed formulation a dosage amount of a functionally active ingredient, an excipient and a polymer or copolymer having a glass transition temperature of about 30° C. to about 150° C., said polymer being present in sufficient quantity to provide from 5% to 50% polymer or copolymer, 1% to 90% excipient, and from 5% to 90% of the functionally active ingredient in the dosage form, processing at least part of the feed formulation into a shaped form and maintaining the shaped form at or above the glass transition temperature of the polymer for from 1 to 12 hours to provide a dosage form having controlled, sustained release of the functionally active ingredient when the dosage form is administered.
 2. A method for preparing a sustained release dosage form comprising blending into a feed formulation a dosage amount of a functionally active ingredient, an excipient and a polymer having a glass transition temperature of 30° C. to 150° C. selected from the group consisting of polyisobutylene, polymers and copolymers of acrylic acid, methacrylic acid, hydroxyalkylacrylic acid, hydroxyalkylmethacrylic acid and their methyl, ethyl and lauryl esters, poly(ethylene oxide), cellulose acetate, cellulose acetate butyrate, cellulose acetate proprionate, ethyl cellulose, polyesters of polyhydric alcohols and dicarboxylic acids, polyethers, cellulose acetate phthalate, dl-polylactic acid, polyglycolic acid, polylactic-polyglycolic copolymers, polycaprolactone, polhydroxybutyrate, polyhydroxyvalerate and polyethylene glycols, mixtures and copolymers thereof to provide from 5% to 50% polymer or copolymer, 1% to 90% excipient and 5% to 90% of the functionally active ingredient processing at least part of the feed formulation into a shaped form characterized by maintaining the shaped form at or above the glass transition temperature of the polymer for from 1 to 12 hours to provide a dosage form having controlled, sustained release of the functionally active ingredient when the dosage form is administered in the dosage form.
 3. The sustained release dosage form of claim 1 or 2 characterized in that the polymer or copolymer has a glass transition temperature of 40° C. to 100° C.
 4. The sustained release dosage form of claims 1 or 2 characterized in that the excipient is selected from the group consisting of lactose, dicalcium phosphate, calcium sulfate, sugar, microcrystalline cellulose, gums, methylcellulose, starch, polyvinylpyrrolidone and clay.
 5. The sustained release dosage form of claim 4 characterized in that the form is a tablet, bead, microcapsule, pill or a granule.
 6. The sustained release dosage form of claim 4 characterized in that the pharmaceutically active ingredient is selected from the group consisting of theophylline, quinidine sulfate, propranolol, chlorpheniramine, testosterone and ethenyl estradiol. 